This Project focuses on the mechanisms by which beta amyloid (A) accumulation and inflammation (specifically interieukin 1 beta; IL-1) impair plasticity and neuronal health. We propose that these molecules interfere with endosomal trafficking of brain-derived neurotrophic factor (BDNF) and its receptor TrkB, leading to impaired neuronal health, function and synaptic plasticity. Our data reveal that IL-1 and A both interfere with retrograde axonal flow of BDNF-TrkB and impair events downstream from BDNF-TrkB signaling, including nuclear gene transcription. In addition, we found that IL-1 impairs the stabilization of BDNF-dependent long-term potentiation (LTP) by preventing actin polymerization in spines. These data indicate that A and IL-i deteriorate synapses by targeting both pre and post-synaptic components, impairing signal transduction and synaptic plasticity and placing neurons at risk for degeneration. We propose that impairment of endosomal trafficking is a common mechanism by which A and IL-1 impair retrograde signaling and spine plasticity. Supporting the hypothesis that dysfunctional endosomal trafficking is an important contributor to AD pathogenesis, several recently identified genetic risk factors for AD impact function of endocytotic pathways (e.g., PICALM, BINI, CD2AP). In this proposal, we will evaluate how A and IL-1 impair endosomal trafficking, focusing on BDNF-TrkB trafficking, and investigate how signaling events downstream of BDNF-TrkB are impacted. Specifically, in Aim 1, we will evaluate mechanisms by which A and IL-1 interfere with endosomal trafficking and axonal retrograde transport of BDNF-TrkB.In Aim 2, we will determine if IL-1 impairs postsynaptic activity-dependent BDNF-TrkB trafficking and plasticity in dendritic spines. We also will eviaute how PICALM can modulate BDNF TrkB trafficking.. Aim 3 will translate the in-vitro data to an in-vivo paradigm, to investigate if IL-1 impairs hippocampal-dependent learning and if select intervention strategies can protect against the detrimental effects of IL-1 on endosomal trafficking, and learning. Our project incorporates data sharing and multiple collaborations with the team: e.g., Glabe (effects of A oligomeric species on BDNF-TrkB trafficking), LaFeria (IL-1, A and endocytic dysfunction). Tenner (Clq protection from IL-1 evoked impairments of BDNF-TrkB F signaling), and Cribbs (impairment of endosomal function by IL-1 and A in endothelial cells).